Systemic fungal infections are increasingly common, especially in immune compromised patients. While new antifungal drugs have been developed, there is still a high mortality associated with these infections, especially those due to Candida albicans, other non-albicans species (NAS). This is due to the limited spectrum of the drugs, significant side effects, as well as the development of resistance, leading to an increase in drug-resistant strains. Host defense proteins (HDPs) are naturally occurring, broad-spectrum antimicrobial agents that have been examined recently for their utility as therapeutic antibiotics and antifungals. Chief among their strengths is that microbes do not generally develop resistance to these agents. Unfortunately, they are expensive to produce and are often sensitive to protease digestion. We have demonstrated the potent activity of a series of inexpensive non-peptidic oligomers and compounds that mimic HDPs in both structure and activity against clinical strains of C. albicans associated with oral candidiasis, both in vitro and in vivo. Our preliminary data demonstrate similar antifungal activity for several mimetics against clinical isolates of C. albicans in the presence of human serum and one of these compounds was robustly efficacious in a mouse of disseminated candidiasis. We believe these compounds can form the basis for the development of novel therapies against systemic fungal infections. Our goal is to identify a safe and efficacious HDP mimic(s) as a development lead for treatment of disseminated candidiasis.